ISIS 5132 is well tolerated at doses up to 6.0 mg/kg when administered as a thrice weekly 2-hour infusion for 3 consecutive weeks. The pharmacokinetic behavior of the drug is reproducible, and suppression of target gene expression is observed in circulating PBMCs.

Angiogenesis inhibition has been shown to enhance the therapeutic efficacy of cytotoxic chemotherapy in colorectal cancer. The basis of the contribution of this modality has not been defined fully. To determine the potential role of hypoxia-induced apoptosis, we studied a series of colon cancer cell lines with varying susceptibility to hypoxia. We exposed HT29 and HCT116 colon adenocarcinoma cell lines to sublethal periods of hypoxia three times weekly for 40 exposures, and derived cell lines both more resistant (from HT29) and more sensitive (from HCT116) to hypoxia-induced apoptosis. Both hypoxia-derived cell lines demonstrated more rapid growth than the parental lines when implanted subcutaneously in immunodeficient mice. Treatment of tumor-bearing mice with bevacizumab resulted in depletion of tumor microvasculature, upregulation of Hypoxia-inducible factor-1 alpha (HIF-1alpha), and increased pimonidazole staining, consistent with an anti-angiogenic effect and induction of hypoxia in tumors derived from all cell lines. The proportion of apoptotic cells was increased in all the treated tumors, and was most pronounced in the bevacizumab-treated HCT116-derived cells. The bevacizumab-treated tumors showed growth delay in HT29 and its derivative, and the parental HCT116. In the hypoxia-sensitive HCT116-derived tumors, marked tumor shrinkage and prolonged growth control occurred. Therefore, bevacizumab treatment is an effective inducer of a hypoxic environment, but the resulting cell kill and tumor shrinkage is determined by the susceptibility of the tumor to apoptosis. The induction of apoptosis by hypoxia may contribute to the benefits of such treatment in the clinical setting.

Background: In this study, we tested the hypothesis that miR-181a levels increase during acute myocardial infarction. We investigated circulating miR-181a as a potential novel biomarker for early diagnosis of acute myocardial infarction (AMI). Methods: From June 2014 to June 2016, 120 consecutive eligible patients with AMI (n = 60) or unstable angina (UA; n = 60) and 60 control subjects were enrolled. Plasma miR-181a levels were determined by quantitative reverse transcriptase-polymerase chain reaction. Results: Circulating miR-181a expression levels detected immediately after admission were higher in the AMI group than in the UA and control groups. Relative miR-181a levels in AMI patients were positively correlated with the concentrations of the creatine kinase-MB fraction and cardiac troponin I. Correlation analysis showed that plasma miR-181a was positively correlated with coronary Gensini score (r = 0.573, P < 0.05) and negatively correlated with left ventricular ejection fraction (r = -0.489, P < 0.05). Receiver operating characteristic curve analyses showed that plasma miR-181a was of significant diagnostic value for AMI (AUC, 0.834; 95% CI, 0.756-0.912, P < 0.05). Conclusion: Circulating miR-181a levels in patients with AMI were significantly changed in a time-dependent manner, indicating the value of plasma miR-181a as a novel biomarker for diagnosing AMI.